Progression Of Bronchopulmonary Dysplasia Research Articles

BCL6 attenuates hyperoxia-induced lung injury by inhibiting NLRP3-mediated inflammation in fetal mouse

Background The transcriptional repressor B-cell lymphoma 6 (BCL6) has been reported to inhibit inflammation. So far, experimental evidence for the role of BCL6 in bronchopulmonary dysplasia (BPD) is lacking. Our study investigated the roles of BCL6 in the progression of BPD and its downstream mechanisms. Methods Hyperoxia or lipopolysaccharide (LPS) was used to mimic the BPD mouse model. To investigate the effects of BCL6 on BPD, recombination adeno-associated virus serotype 9 expressing BCL6 (rAAV9-BCL6) and BCL6 inhibitor FX1 were administered in mice. The pulmonary pathological changes, inflammatory chemokines and NLRP3-related protein were observed. Meanwhile, BCL6 overexpression plasmid was used in human pulmonary microvascular endothelial cells (HPMECs). Cell proliferation, apoptosis, and NLRP3-related protein were detected. Results Either hyperoxia or LPS suppressed pulmonary BCL6 mRNA expression. rAAV9-BCL6 administration significantly inhibited hyperoxia-induced NLRP3 upregulation and inflammation, attenuated alveolar simplification and dysregulated angiogenesis in BPD mice, which were characterized by decreased mean linear intercept, increased radical alveolar count and alveoli numbers, and the upregulated CD31 expression. Meanwhile, BCL6 overexpression promoted proliferation and angiogenesis, inhibited apoptosis and inflammation in hyperoxia-stimulated HPMECs. Moreover, administration of BCL6 inhibitor FX1 arrested growth and development. FX1-treated BPD mice exhibited exacerbation of alveolar pathological changes and pulmonary vessel permeability, with upregulated mRNA levels of pro-inflammatory cytokines and pro-fibrogenic factors. Furthermore, both rAAV9-BCL6 and FX1 administration exerted a long-lasting effect on hyperoxia-induced lung injury (≥4 wk). Conclusions BCL6 inhibits NLRP3-mediated inflammation, attenuates alveolar simplification and dysregulated pulmonary vessel development in hyperoxia-induced BPD mice. Hence, BCL6 may be a target in treating BPD and neonatal diseases.

Cellular Senescence Contributes to the Progression of Hyperoxic Bronchopulmonary Dysplasia.

Oxidative stress, inflammation, and endoplasmic reticulum (ER) stress sequentially occur in bronchopulmonary dysplasia (BPD), and all result in DNA damage. When DNA damage becomes irreparable, tumor suppressors increase, followed by apoptosis or senescence. Although cellular senescence contributes to wound healing, its persistence inhibits growth. Therefore, we hypothesized that cellular senescence contributes to BPD progression. Human autopsy lungs were obtained. Sprague-Dawley rat pups exposed to 95% oxygen between Postnatal Day 1 (P1) and P10 were used as the BPD phenotype. N-acetyl-lysyltyrosylcysteine-amide (KYC), tauroursodeoxycholic acid (TUDCA), and Foxo4 dri were administered intraperitoneally to mitigate myeloperoxidase oxidant generation, ER stress, and cellular senescence, respectively. Lungs were examined by histology, transcriptomics, and immunoblotting. Cellular senescence increased in rat and human BPD lungs, as evidenced by increased oxidative DNA damage, tumor suppressors, GL-13 stain, and inflammatory cytokines with decreased cell proliferation and lamin B expression. Cellular senescence-related transcripts in BPD rat lungs were enriched at P10 and P21. Single-cell RNA sequencing showed increased cellular senescence in several cell types, including type 2 alveolar cells. In addition, Foxo4-p53 binding increased in BPD rat lungs. Daily TUDCA or KYC, administered intraperitoneally, effectively decreased cellular senescence, improved alveolar complexity, and partially maintained the numbers of type 2 alveolar cells. Foxo4 dri administered at P4, P6, P8, and P10 led to outcomes similar to TUDCA and KYC. Our data suggest that cellular senescence plays an essential role in BPD after initial inducement by hyperoxia. Reducing myeloperoxidase toxic oxidant production, ER stress, and attenuating cellular senescence are potential therapeutic strategies for halting BPD progression.

Tat-P combined with GAPR1 releases Beclin1 to promote autophagy and improve Bronchopulmonary dysplasia model

Long-term exposure to hyperoxia can leading to the bronchopulmonary dysplasia (BPD). The progression of BPD is primarily driven by the apoptosis of alveolar epithelial cells, and the regulation of autophagy has an impact on apoptosis. This study aims to investigate the therapeutic potential and underlying mechanism of an autophagy-promoting peptide (Tat-P) in ameliorating BPD. Invitro experiments demonstrated that Tat-P promoted autophagy and partially prevented apoptosis caused by exposure to hyperoxia. Further investigation into the mechanism revealed that Tat-P competitively binds to GAPR1, displacing the Beclin1 protein and thereby inhibiting the apoptosis. Invivo experiments conducted on Sprague-Dawley pups exposed to high oxygen levels demonstrated that Tat-P promoted autophagy and reduced apoptosis in lung tissues and ameliorated BPD-related phenotypes. Our findings elucidate the underlying mechanisms and effects of Tat-P in enhancing autophagy and preventing apoptosis. This study presents an approach for the prevention and treatment of BPD.

Lung ultrasound assessment of pulmonary edema in neonates with chronic lung disease before and after diuretic therapy.

Bronchopulmonary dysplasia (BPD) is characterized by lung injury with varying degrees of disrupted alveolarization, vascular remodeling, inflammatory cell proliferation, and pulmonary edema. Diuretics are often used to ameliorate the symptoms or progression of BPD. Our primary objective was to use lung ultrasound (LUS) to determine if diuretics decrease pulmonary edema in infants with BPD. The secondary objective was to assess changes in respiratory support during the first week after initiation of diuretics. Premature infants requiring noninvasive respiratory support and starting diuretic therapy for evolving BPD were compared with a similar group of infants not receiving diuretics (control). For the diuretic group, LUS exams were performed before and on Days 1, 3, and 6 after initiation of treatment. For the control group, LUS was performed at equivalent time points. A composite pulmonary edema severity (PES) score of 0-5 was calculated based on the total number of B-lines in six scanned areas. Respiratory support parameters (FiO2 , nasal cannula flow, or CPAP) were also recorded. Infants in the diuretic (n = 28) and control (n = 23) groups were recruited at median corrected gestational ages of 34.2 (33.3-35.9) and 34.0 (33.4-36.3) weeks, respectively (p = 0.82). PES scores, FiO2 , and respiratory flow support decreased significantly from Days 0 to 6 (p < 0.0001, p = 0.001, and p = 0.01, respectively) in the diuretic group, but not in the control group. Diuretic use is associated with decreased pulmonary edema and improved oxygenation in infants with BPD during the first week of treatment.

Expression of long noncoding RNA uc.375 in bronchopulmonary dysplasia and its function in the proliferation and apoptosis of mouse alveolar epithelial cell line MLE 12.

Background: According to our previous gene ChIP results, long noncoding RNA uc.375 was down-regulated in lung tissue of bronchopulmonary dysplasia (BPD) mice induced by hyperoxia. FoxA1 gene showed higher levels in lung tissue of BPD mice and is reported to promote the apoptosis of alveolar epithelial cells. We aimed to clarify the expression pattern of uc.375 in BPD and explore the interaction between uc.375 and FoxA1. Methods: Newborn mice were placed in a 95% high-oxygen environment for 7 days. Lung tissue samples from mice were used for lncRNA microarray to screen BPD related lncRNAs. Mouse alveolar epithelial cell line MLE 12 was stably transfected with uc.375 and FoxA1 silencing or overexpression lentiviral vectors. The proliferation activity of MLE 12 cells was detected by a cell counting kit 8 (CCK-8) assay. MLE 12 cell apoptosis was determined by Hoechst/PI staining and flow cytometry analysis. The protein levels of Cleaved Caspase-3, FoxA1, SP-C and UCP2 were investigated by western blot. The relative mRNA expression levels were detected by quantitative real-time PCR. Results: uc.375 is mainly distributed in the nucleus of alveolar epithelial cells, as revealed by In Situ Hybridization assay results. uc.375 was lowly expressed in the lung tissues of BPD mice. According to the results of CCK-8 assay, analysis of Hoechst/PI staining and western blotting, uc.375 silencing inhibited cell proliferation, facilitated apoptosis of MLE 12 cells, promoted caspase 3 and FoxA1 expression, and inhibited the expression of SP-C and UCP2. On the contrary, after overexpressing uc.375, the opposite results were obtained. Silencing FoxA1 inhibited MLE 12 apoptosis, promoted proliferation, inhibited apoptosis-related factor caspase 3, and promoted the expression of SP-C and UCP2. FoxA1 silencing also reversed the effect induced by uc.375 knockdown on the proliferation and apoptosis of MLE 12 cells. Conclusion: Based on the biomedical images-derived analysis results, uc.375 negatively regulates FoxA1 expression, affects alveolar development, and plays an important role in the initiation and progression of BPD, providing a new molecular target for the prevention and treatment of BPD.

Long non‑coding RNA Rian protects against experimental bronchopulmonary dysplasia by sponging miR‑421

Bronchopulmonary dysplasia (BPD) is a frequent complication characterized by accelerated lung alveolarization in newborns. Long non-coding RNAs (lncRNAs) and microRNAs (miRs) are regarded as essential regulators in various diseases, including BPD. However, the detailed mechanism of the functions of RNA imprinted and accumulated in nucleus (Rian) lncRNA in the progression of BPD have remained elusive. The aim of the present study was to illustrate the interaction between miR-421 and Rian in BPD models and MLE-12 cells. The ability of Rian to protect neonatal lungs from hyperoxia-induced lung damage was examined. A mouse model of BPD and a hyperoxia-stimulated MLE-12 cell damage model were generated and treated with specific plasmid/mimics for the overexpression of Rian/miR-421. The interaction between miR-421 and Rian was predicted and verified using StarBase and a dual-luciferase reporter assay, respectively. The expression levels of miR-421 or Rian in both tissues and the MLE-12 alveolar epithelial cell line were assessed using reverse transcription-quantitative (RT-q)PCR. As parameters of alveolarization, the mean linear intercept (MLI), radial alveolar count (RAC) and the lung weight/body weight (LW/BW) ratio were measured. Furthermore, RT-qPCR was used to measure mRNA levels of pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β) in the lung tissue of mice, and ELISAs were performed to determine the levels of pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β) in the supernatant of MLE-12 cells. Cell growth and apoptosis were evaluated using an MTT assay and flow cytometry, respectively. Furthermore, caspase-3 activity was assessed using a caspase-3 activity detection kit. Prediction with StarBase and the dual-luciferase reporter assay revealed that miR-421 directly targeted Rian. RT-qPCR analysis confirmed that Rian was downregulated and miR-421 was upregulated in lung tissues of the mouse model of BPD and in hyperoxia-induced MLE-12 cells. However, the expression of miR-421 was decreased by Rian-overexpression, an effect that was reversed by miR-421 mimics. In addition, BPD was alleviated by Rian-plasmid, as confirmed by the enhanced RAC and reduced MLI and LW/BW ratio. The present results also indicated that Rian-plasmid inhibited the secretion of pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β) in BPD mouse serum and hyperoxia-induced MLE-12 cells. In addition, Rian-plasmid eliminated the effect of hyperoxia to inhibit cell viability and induce apoptosis in MLE-12 cells. However, all of these effects of Rian were markedly reversed by miR-421 mimics. The present results indicated that Rian may attenuate hyperoxic damage in neonatal lungs and may serve as a novel molecular target for BPD treatment.

Effect of antibiotic-induced intestinal dysbacteriosis on bronchopulmonary dysplasia and related mechanisms

BackgroundModification of the gut microbiota by antibiotics may influence the disease susceptibility and immunological responses. Infants in the neonatal intensive care unit (NICU) subjected to frequent antibiotics and oxygen therapies, which may give rise to local and systemic inflammatory reactions and progression of bronchopulmonary dysplasia (BPD). This study aimed to investigate the role of intestinal dysbacteriosis by antibiotic therapy before hyperoxia exposure in the progression of BPD.MethodsMice had been exposed to hyperoxia (85% O2) since postnatal day 3 until day 16 for the BPD model establishment, treated with antibiotics from postnatal day 2 until day 8. Treated mice and appropriate controls were harvested on postnatal day 2 or 10 for 16S rRNA gene sequencing, or postnatal day 17 for assessment of alveolar morphometry and macrophages differentiation.ResultsAntibiotic-induced intestinal dysbacteriosis before hyperoxia exposure gave rise to deterioration of BPD evidenced by reduced survival rates and alveolarization. Moreover, antibiotic-induced intestinal dysbacteriosis resulted in increased M1 macrophage maker (iNOS) and decreased M2 macrophage maker (Arg-1) levels in lung homogenates.ConclusionBroad-spectrum antibiotic-induced intestinal dysbacteriosis may participate in BPD pathogenesis via alteration of the macrophage polarization status. Manipulating the gut microbiota may potentially intervene the therapy of BPD.

Interleukin-24 as a Pulmonary Target Cytokine in Bronchopulmonary Dysplasia.

The proliferation of fetal alveolar type II cells (FATIICs) was impaired in bronchopulmonary dysplasia (BPD), which is modulated by hyperoxia and inflammatory response. Interleukin 24 (IL-24), a cytokine produced by certain cell types, plays an essential role in inflammation and host protection against infection. However, the ability of FATIICs to produce IL-24 remains unclear, and the role of IL-24 in BPD progression is yet to be determined. With reverse transcription quantitative polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay, the authors evaluated whether FATIICs produce IL-24 in physiological conditions. The authors quantified IL-24 expression in the lungs of newborn rat pups exposed to hyperoxia (70% oxygen) and in FATIICs isolated on embryonic day 19 that were exposed to 95% oxygen or lipopolysaccharide (LPS). The role of IL-24 in FATIICs, cell proliferation, cell apoptosis, and cell cycle were further evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and flow cytometric analysis. Also, they assessed caspase-3 and SOCS3 mRNA in IL-24 siRNA-treated cells by using RT-qPCR. During culture, IL-24 mRNA and protein levels in FATIICs gradually decreased with FATIIC differentiation. IL-24 expression increased significantly in rat lungs exposed to hyperoxia and FATIICs exposed to oxygen or LPS. Recombinant IL-24 enhanced cell proliferation by decreasing the proportion of apoptotic cells and increasing the proportion of cells in the S phase. The IL-24 siRNA-treated cells expressed more caspase-3 mRNA. Furthermore, suppressor of cytokine signaling 3 (SOCS3) mRNA was significantly decreased in rats and FATIICs exposed to oxygen, whereas it dramatically increased in FATIICs exposed to LPS. The IL-24 siRNA-treated cells expressed more SOCS3 mRNA. These studies suggest IL-24 is a pulmonary target cytokine in BPD, and may possibly regulate SOCS3 in oxidative stress and inflammation of the lung.

Knockdown of miR-203a-3p alleviates the development of bronchopulmonary dysplasia partly via the up-regulation of vascular endothelial growth factor A.

Bronchopulmonary dysplasia (BPD) is characterized by impaired vascular and alveolar development, and the underlying molecular mechanisms have remained elusive. MicroRNAs are important players in various biological functions including the pathogenesis of BPD. The present study aimed to examine the expression of miR-203a-3p in the peripheral blood of BPD patients and elucidate the mechanisms underlying miR-203a-3p-mediated progression of BPD. We examined the expression of miR-203a-3p in the peripheral blood of BPD patients and found that miR-203a-3p was up-regulated in the patients. Additionally, the mRNA expression levels of vascular endothelial growth factor A (VEGFA) and hypoxia-inducible factor-1alpha were down-regulated in the BPD patients. Further in vitro studies showed that miR-203a-3p suppressed the expression of VEGFA in RLE-6TN cells by targeting the VEGFA 3' untranslated region. Overexpression of miR-203a-3p inhibited the viability of RLE-6TN cells and induced cell apoptosis, whereas the knockdown of miR-203a-3p exerted opposite effects. VEGFA treatment significantly attenuated the increase in the RLE-6TN cell apoptotic rates induced by miR-203a-3p overexpression; while VEGFA knockdown significantly increased the cell apoptotic rates of RLE-6TN cells, which was partially reversed by the treatment with miR-203a-3p inhibitor. Furthermore, miR-203a-3p was up-regulated, whereas VEGFA was down-regulated in the lung tissues of BPD rats, and sequestration of the expression of miR-203a-3p prevented hyperoxia-induced lung damage, increased VEGFA mRNA and protein expression levels, and promoted the protein expression of ERK, PI3K, and p38 in the lung tissues of BDP rats. In summary, the findings of our study indicate that miR-203a-3p knockdown alleviates hyperoxia-induced lung tissue damage in the BPD rat model, and its effect may be associated with the up-regulation of VEGF.

The high-risk factors of different severities of bronchopulmonary dysplasia (BPD) based on the national institute of child health and human development (NICHD) diagnosis criteria in 2018.

ABSTRACTObjectiveTo investigate the clinical characteristics of preterm infants with different severities of bronchopulmonary dysplasia (BPD) and disclose the high-risk factors of exacerbating BPD.MethodsCollection of clinical data of 91 preterm infants admitted to the NICU and diagnosed with BPD, categorized in groups according to the disease severity: 41 mild cases,, 24 moderate cases, and 26 severe cases. Comparison and analysis of perinatal risk factors, treatment, complications and prognosis of the infants with different severity degrees.ResultsThe severe group had a higher proportion of infants with congenital heart disease (CHD) higher than the moderate group (P < 0.05), and a higher ratio of pneumonia and mechanical ventilation (MV) ≥ seven days than the mild group (P < 0.05). The severe group also presented higher reintubation incidence than both the mild and moderate groups (P < 0.05). The groups presented different (P < 0.05) incidence rates of hemodynamically significant patent ductus arteriosus (hsPDA) . Ridit analysis suggested that the premature infants (PIs) with hsPDA, multiple microbial pulmonary infections, or Klebsiella pneumoniae pneumonia had more severe illness.ConclusionCHD, hsPDA, MV ≥ seven days, reintubation, pneumonia, especially multiple microbial pulmonary infections, and Klebsiella pneumoniae pneumonia are correlated with the severity of BPD and can be used as BPD progression predictor.

Involvement of Hdac3-mediated inhibition of microRNA cluster 17-92 in bronchopulmonary dysplasia development

BackgroundThe incidence of bronchopulmonary dysplasia (BPD), a chronic lung disease of newborns, has been paradoxically rising despite medical advances. Histone deacetylase 3 (Hdac3) has been reported to be a crucial regulator in alveologenesis. Hence, this study aims to investigate the mechanism of Hdac3 in the abnormal pulmonary angiogenesis and alveolarization of BPD.MethodsA hyperoxia-induced BPD model of was developed in newborn mice, and primary lung fibroblasts were isolated from adult mice. Hdac3 was knocked out in vivo and knocked down in vitro, while microRNA (miR)-17 was downregulated in vivo and in vitro to clarify their roles in abnormal pulmonary angiogenesis and alveolarization. Mechanistic investigations were performed on the interplay of Hdac3, miR-17-92 cluster, enhancer of zeste homolog 1 (EZH1), p65 and placental growth factor (Pgf).ResultsHdac3 was involved in abnormal alveolarization and angiogenesis in BPD mice. Further, the expression of the miR-17-92 cluster in BPD mice was downregulated by Hdac3. miR-17 was found to target EZH1, and Hdac3 rescued the inhibited EZH1 expression by miR-17 in lung fibroblasts. Additionally, EZH1 augmented Pgf expression by recruiting p65 thus enhancing the progression of BPD. Hdac3 augmented the recruitment of p65 in the Pgf promoter region through the miR-17/EZH1 axis, thus enhancing the transcription and expression of Pgf, which elicited abnormal angiogenesis and alveolarization of BPD mice.ConclusionsAltogether, the present study revealed that Hdac3 activated the EZH1-p65-Pgf axis through inhibiting miR-17 in the miR-17-92 cluster, leading to accelerated abnormal pulmonary angiogenesis and alveolarization of BPD mice.

Weighted Gene Co-expression Network Analysis of Key Biomarkers Associated With Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD) is a complex disorder resulting from interactions between genes and the environment. The accurate molecular etiology of BPD remains largely unclear. This study aimed to identify key BPD-associated genes and pathways functionally enriched using weighted gene co-expression network analysis (WGCNA). We analyzed microarray data of 62 pre-term patients with BPD and 38 pre-term patients without BPD from Gene Expression Omnibus (GEO). WGCNA was used to construct a gene expression network, and genes were classified into definite modules. In addition, the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of BPD-related hub genes were performed. Firstly, we constructed a weighted gene co-expression network, and genes were divided into 10 modules. Among the modules, the yellow module was related to BPD progression and severity and included the following hub genes: MMP25, MMP9, SIRPA, CKAP4, SLCO4C1, and SLC2A3; and the red module included some co-expression molecules that displayed a continuous decline in expression with BPD progression and included the following hub genes: LEF1, ITK, CD6, RASGRP1, IL7R, SKAP1, CD3E, and ICOS. GO and KEGG analyses showed that high expression of inflammatory response-related genes and low expression of T cell receptor activation-related genes are significantly correlated with BPD progression. The present WGCNA-based study thus provides an overall perspective of BPD and lays the foundation for identifying potential pathways and hub genes that contribute to the development of BPD.

Montelukast improves bronchopulmonary dysplasia by inhibiting epithelial‑mesenchymal transition via inactivating the TGF‑β1/Smads signaling pathway.

The present study investigated the role of montelukast (MK) during the progression of bronchopulmonary dysplasia (BPD) and the underlying mechanism of action. A rat model of BPD was induced by hyperoxia and subsequently, the rats were treated with 10mg/kg MK. On day 14 post‑hyperoxia induction, lung function was assessed by detecting the mean linear intercept (MLI; the average alveolar diameter), the radial alveolar count (RAC; alveolar septation and alveologenesis) and the lung weight/body weight (LW/BW) ratio. Type II alveolar epithelial (AEC II) cells were isolated from normal rats to investigate the mechanism underlying the effect of MK on BPD invitro. Western blotting and reverse transcription‑quantitative PCR were performed to measure the expression levels of surfactant protein C (SP‑C), E‑cadherin, N‑cadherin, Vimentin, collagen I (Col I), matrix metallopeptidase (MMP)1/3, transforming growth factor (TGF)‑β1 and Smad3. MK significantly reduced the MLI and the LW/BW ratio, and increased the RAC of the BPD group compared with the control group. MK upregulated the expression of SP‑C and E‑cadherin, and downregulated the expression levels of N‑cadherin and Vimentin in the lung tissues of the rat model of BPD, as well as in TGF‑β1‑ and hyperoxia‑induced AEC II cells. In addition, MK reduced the expression of Col I, MMP1, MMP3, TGF‑β1 and Smad3 in the lung tissues of the rat model of BPD, as well as in TGF‑β1‑ and hyperoxia‑induced AEC II cells. The present study demonstrated that MK improved BPD by inhibiting epithelial‑mesenchymal transition via inactivating the TGF‑β1/Smads signaling pathway.

Present and Future of Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD) is the most common respiratory disorder among infants born extremely preterm. The pathogenesis of BPD involves multiple prenatal and postnatal mechanisms affecting the development of a very immature lung. Their combined effects alter the lung’s morphogenesis, disrupt capillary gas exchange in the alveoli, and lead to the pathological and clinical features of BPD. The disorder is ultimately the result of an aberrant repair response to antenatal and postnatal injuries to the developing lungs. Neonatology has made huge advances in dealing with conditions related to prematurity, but efforts to prevent and treat BPD have so far been only partially effective. Seeing that BPD appears to have a role in the early origin of chronic obstructive pulmonary disease, its prevention is pivotal also in long-term respiratory outcome of these patients. There is currently some evidence to support the use of antenatal glucocorticoids, surfactant therapy, protective noninvasive ventilation, targeted saturations, early caffeine treatment, vitamin A, and fluid restriction, but none of the existing strategies have had any significant impact in reducing the burden of BPD. New areas of research are raising novel therapeutic prospects, however. For instance, early topical (intratracheal or nebulized) steroids seem promising: they might help to limit BPD development without the side effects of systemic steroids. Evidence in favor of stem cell therapy has emerged from several preclinical trials, and from a couple of studies in humans. Mesenchymal stromal/stem cells (MSCs) have revealed a reparatory capability, preventing the progression of BPD in animal models. Administering MSC-conditioned media containing extracellular vesicles (EVs) have also demonstrated a preventive action, without the potential risks associated with unwanted engraftment or the adverse effects of administering cells. In this paper, we explore these emerging treatments and take a look at the revolutionary changes in BPD and neonatology on the horizon.

IL-33-induced neutrophil extracellular traps degrade fibronectin in a murine model of bronchopulmonary dysplasia

Bronchopulmonary dysplasia (BPD) is the leading cause of chronic lung disease in preterm neonates. Extracellular matrix (ECM) abnormalities reshape lung development, contributing to BPD progression. In the present study, we first discovered that the ECM component fibronectin was reduced in the pulmonary tissues of model mice with BPD induced by lipopolysaccharide (LPS) and hyper-oxygen. Meanwhile, interleukin-33 (IL-33) and other inflammatory cytokines were elevated in BPD lung tissues. LPS stimulated the production of IL-33 in alveolar epithelial cells via myeloid differentiation factor 88 (MyD88), protein 38 (p38), and nuclear factor-kappa B (NF-κB) protein 65 (p65). Following the knockout of either IL-33 or its receptor suppression of tumorigenicity 2 (ST2) in mice, BPD disease severity was improved, accompanied by elevated fibronectin. ST2 neutralization antibody also relieved BPD progression and restored the expression of fibronectin. IL-33 induced the formation of neutrophil extracellular traps (NETs), which degraded fibronectin in alveolar epithelial cells. Moreover, DNase-mediated degradation of NETs was protective against BPD. Finally, a fibronectin inhibitor directly decreased fibronectin and caused BPD-like disease in the mouse model. Our findings may shed light on the roles of IL-33-induced NETs and reduced fibronectin in the pathogenesis of BPD.

The Role of LncRNA H19 in MAPK Signaling Pathway Implicated in the Progression of Bronchopulmonary Dysplasia

Bronchopulmonary dysplasia (BPD), also known as neonatal chronic lung disease, is an important cause of respiratory illness in preterm newborns that results in significant morbidity and mortality. Long noncoding RNAs (lncRNAs) have been discovered with many biological functions. However, the role of lncRNAs in the pathogenesis of BPD remains poorly understood. Here, we established a mouse lung injury model that mimicked human BPD. Subsequently, we found the lncRNA H19 expression level was significantly increased in BPD compared with normal lung tissues using quantitative real-time polymerase chain reaction. Next, we observed that overexpression of lncRNA H19 enhanced mitogen-activated protein kinase (MAPK) signaling pathway. In addition, we also found that dysfunction of lncRNA H19 altered the expression of inflammatory factors. Thus, our study validates that lncRNA H19 contributes to the progression of BPD by regulating MAPK signaling pathway, which could be used as a potential target for treating BPD.

MicroRNA-421 inhibition alleviates bronchopulmonary dysplasia in a mouse model via targeting Fgf10.

Bronchopulmonary dysplasia (BPD) is a common and refractory disease affecting newborn children and infants with alveolar dysplasia and declined pulmonary function. Several microRNAs (miRNAs) have been found to be differentially expressed in BPD progression. This study further explores the role of miR-421 via fibroblast growth factor 10 (Fgf10) in mice with BPD. A mouse model of BPD was established through the induction of hyperoxia, in which the expression pattern of miR-421 and Fgf10 was identified. Furthermore, adenovirus-packed vectors were injected in mice to intervene miR-421 and Fgf10 expression, including miR-421 mimics or inhibitors, and si-Fgf10 to explore the role of miR-421 and Fgf10 in BPD. The target relationship between miR-421 and Fgf10 was investigated. Inflammatory response and cell apoptosis were observed in the mice, with inflammatory cytokines and apoptosis-related factors detected by applying Reverse transcription quantitative polymerase chain reaction, Western blot analysis, and enzyme-linked immunosorbent assay. Fgf10 was confirmed as a target gene of miR-421. Elevated expression of miR-421 was evident, while Fgf10 was poorly expressed in BPD. upregulation of miR-421 and silence of Fgf10 aggravated inflammatory response in lung tissue and promoted lung cell apoptosis in BPD. The aforementioned alterations could be reversed by downregulation of miR-421. Collectively, inhibition of miR-421 can assist in the development of BPD in mice BPD by upregulating Fgf10. Therefore, the present study provides a probable target for the treatment of BPD.

Airway Microbiome and Development of Bronchopulmonary Dysplasia in Preterm Infants: A Systematic Review

To summarize evidence regarding microbial dysbiosis of the airway associated with bronchopulmonary dysplasia (BPD) and to explore heterogeneity among studies. We included studies that evaluated the airway microbiome in preterm infants who developed BPD using culture-independent molecular techniques and reported alpha- and beta-diversity metrics and microbial profiles. The 6 included studies had substantial clinical and methodological heterogeneity. Most studies reported the presence of an airway microbiome early after birth and an evolution in the first weeks of life with increasing bacterial loads. The early airway microbiome was dominated by Staphylococcus and Ureaplasma spp. Two studies reported differences in alpha- and beta- diversity indices in preterm infants with BPD compared with those who did not develop BPD. Increased microbial community turnover, changes in the relative abundance of Proteobacteria and Firmicutes, and decreased Lactobacilli were reported with BPD progression. Most included infants were born by cesarean delivery, and a majority were exposed to postnatal antibiotics. No data regarding feeding human milk or correlations with the development of gut microbiota (gut-lung axis) were available. Microbial dysbiosis may be associated with BPD progression and severity, and further study of microbiome optimization in preterm infants at risk for BPD is warranted.

Endothelial Monocyte-Activating Polypeptide II Mediates Macrophage Migration in the Development of Hyperoxia-Induced Lung Disease of Prematurity.

Myeloid cells are key factors in the progression of bronchopulmonary dysplasia (BPD) pathogenesis. Endothelial monocyte-activating polypeptide II (EMAP II) mediates myeloid cell trafficking. The origin and physiological mechanism by which EMAP II affects pathogenesis in BPD is unknown. The objective was to determine the functional consequences of elevated EMAP II levels in the pathogenesis of murine BPD and to investigate EMAP II neutralization as a therapeutic strategy. Three neonatal mouse models were used: (1) BPD (hyperoxia), (2) EMAP II delivery, and (3) BPD with neutralizing EMAP II antibody treatments. Chemokinic function of EMAP II and its neutralization were assessed by migration in vitro and in vivo. We determined the location of EMAP II by immunohistochemistry, pulmonary proinflammatory and chemotactic gene expression by quantitative polymerase chain reaction and immunoblotting, lung outcome by pulmonary function testing and histological analysis, and right ventricular hypertrophy by Fulton's Index. In BPD, EMAP II initially is a bronchial club-cell-specific protein-derived factor that later is expressed in galectin-3+ macrophages as BPD progresses. Continuous elevated expression corroborates with baboon and human BPD. Prolonged elevation of EMAP II levels recruits galectin-3+ macrophages, which is followed by an inflammatory state that resembles a severe BPD phenotype characterized by decreased pulmonary compliance, arrested alveolar development, and signs of pulmonary hypertension. In vivo pharmacological EMAP II inhibition suppressed proinflammatory genes Tnfa, Il6, and Il1b and chemotactic genes Ccl2 and Ccl9 and reversed the severe BPD phenotype. EMAP II is sufficient to induce macrophage recruitment, worsens BPD progression, and represents a targetable mechanism of BPD development.

Bronchopulmonary dysplasia: new becomes old again!

Despite the many advances in neonatology, bronchopulmonary dysplasia (BPD) continues to be a frustrating disease of prematurity. BPD is a disease which is defined oddly by its treatment rather than its pathophysiology, leading to frequently changing nomenclature which has widespread implications on our ability to both understand and follow the progression of BPD. As various treatment modalities for BPD were developed and a larger number of extremely preterm infants survived, the "old" BPD based on lung injury from oxygen therapy and mechanical ventilation transitioned into a "new" BPD focused more on the interruption of normal development. However, the interruption of normal development does not solely apply to lung development. The effects of prematurity on vascular development cannot be overstated and pulmonary vascular disease has become the new frontier of BPD. As we begin to better understand the complex, multifactorial pathophysiology of BPD, it is necessary to again focus on appropriate, pathology-driven nomenclature that can effectively describe the multiple clinical phenotypes of BPD.